title: Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines.
abstract: Cancer cells genetically modified to secrete immunoregulatory cytokines offer great promise for human cancer treatment as tumor vaccines. However, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccine therapy tends to cure only animals bearing 1 x 10(5) wild-type CT26 cells or less. For many human cancers, antineoplastic chemotherapy can often significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the breast, colon, and prostate, antineoplastic drug treatments generally fail to effect cancer cures. Treatment regimens combining genetically-modified cancer cell vaccine therapy and antineoplastic chemotherapy have the potential to increase advanced cancer cure rates if antineoplastic drugs and drug combinations that do not inhibit vaccine-induced immune responses can be identified. To assess the potential immunomodulatory properties of commonly-used antineoplastic drugs that might be used in combination with cancer vaccine treatments, we studied the effects of the drugs on antitumor immune responses manifest by animals receiving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunomodulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytotoxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculac of CT26 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxorubicin was found to possess apparent immunostimulatory activities, depending on the dose and schedule of administration, while cyclophosphamide appeared immunosuppressive. The different immunomodulatory properties of doxorubicin and cyclophosphamide may be clinically relevant: combination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, while combination cyclophosphamide and vaccine treatment of animals carrying CT26 tumors was no better in curing the animals than drug treatment alone.
authors.affiliation: Departments of Oncology, Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nigam
authors.forename: R F
authors.initials: RF
authors.lastname: Yacavone
authors.forename: M L
authors.initials: ML
authors.lastname: Zahurak
authors.forename: C M
authors.initials: CM
authors.lastname: Johns
authors.forename: D M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: H I
authors.initials: HI
authors.lastname: Levitsky
authors.forename: W G
authors.initials: WG
authors.lastname: Nelson
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D012333:RNA, Messenger; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide